Therapeutic effects of CORM3 and NaHS in chronic kidney disease induced cognitive impairment via the interaction between carbon monoxide and hydrogen sulfide on Nrf2/HO-1 signaling pathway in rats

• Published in: Chemico-biological interactions Vol. 368; p. 110217
• Main Authors: Hamidizad, Zeinab, Kadkhodaee, Mehri, Karimian, Seyed Morteza, Ranjbaran, Mina, Heidari, Fatemeh, Bakhshi, Enayatollah, Kianian, Farzaneh, Zahedi, Elham, Seifi, Behjat
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2022
• Subjects: Carbon monoxide; Chronic kidney disease; Cognitive impairment; Hydrogen sulfide; Nrf2/HO-1 signaling pathway; Hydrogen sulfide; Chronic kidney disease; Carbon monoxide; Nrf2/HO-1 signaling pathway; Cognitive impairment
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2022.110217

Cognitive impairment is one of the major complications of chronic kidney disease (CKD). The present study aims to evaluate the protective effects of carbon monoxide (CO) and hydrogen sulfide (H2S) and their interactions on CKD-induced cognitive deficits by considering the Nrf2/HO-1 signaling pathway. Sixty rats were divided into six experimental groups: sham, five-sixth (5/6) nephrectomy (CKD), CKD + H2S donor (NaHS), CKD + CO-releasing molecule (CORM3), CKD + NaHS and zinc protoporphyrin IX (Znpp), CKD + CORM3 and amino-oxy acetic acid (AOAA). Eleven weeks after 5/6Nx, behavioral tests (Novel object recognition test, Passive avoidance test and Barnes maze test) were performed to evaluate the cognitive level. At the end of the twelfth week, blood urea nitrogen (BUN) and serum creatinine (sCr) levels, as well as the expression levels of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and neuronal loss in the hippocampus and prefrontal cortex were evaluated. CKD caused enhancement of BUN and sCr, reduction of Nrf2 and HO-1 proteins and enhancement of neuronal loss in the hippocampus and prefrontal cortex. In addition, CKD led to cognitive disturbances and memory impairment. CORM3 and NaHS returned all above indices to the levels measured in the control group. However, improving effects of CORM3 on cognitive impairment and Nrf2/HO-1 signaling pathway were prevented by AOAA and decreased H2S level as well as reciprocally improving effects of NaHS on cognitive disturbances and Nrf2/HO-1 signaling pathway were prevented by Znpp and decreased CO level. In conclusion, this study demonstrated that formation of CO and H2S were interdependently improved CKD-induced cognitive dysfunctions, through interaction with Nrf2/HO-1 signaling pathway. •CKD causes cognitive impairment partially through disruption of the Nrf2/HO-1 signaling pathway.•CORM3 or NaHS ameliorates CKD-induced cognitive impairment by modulating the Nrf2/HO-1 signaling pathway.•The modulating effects of CORM3 on the Nrf2/HO-1 signaling pathway are partly mediated through H2S.•The modulating effects of NaHS on the Nrf2/HO-1 signaling pathway are mediated in part through CO.